Trends in Pharmacological Sciences
ReviewHistamine receptors in the CNS as targets for therapeutic intervention
Section snippets
Histamine receptors
Four metabotropic histaminergic receptors have been cloned (H1R, H2R, H3R and H4R) that are all expressed in distinctive patterns and density in the brain. H1Rs couple to Gαq/11 proteins to activate phospholipase C [7]. Other effector pathways of H1Rs include production of arachidonic acid, nitric oxide and cGMP [7]. H1Rs are found throughout the central nervous system (CNS) with particularly high densities in brain regions concerned with behavioral and nutritional state control, and their
The H3R as an attractive drug target in the brain
The pharmacological features of the H3R render it a very attractive target for the potential treatment of several CNS diseases, despite the fact that no neurological disorders have been directly ascribed to histaminergic dysfunctions. The H3R acts as an autoreceptor and also moderates the release of other neurotransmitters, including acetylcholine (ACh), dopamine, GABA, 5-hydroxytryptamine and peptides [7]. On histaminergic neuron endings, H3R activation moderates histamine synthesis and
Heterogeneous functions of histamine neurons and their therapeutic implications
The intuition that histamine might be a neurotransmitter dates back to the pioneering work of Schwartz and colleagues [26], and two independent neuroanatomical studies that unequivocally proved the existence of histaminergic neurons 27, 28. The cell bodies of histaminergic neurons are restricted to discrete cell clusters in the hypothalamic tuberomammillary nucleus (TMN) and send their axons to innervate nearly the entire CNS, with a cytoarchitecture comparable to dopaminergic, noradrenergic
Histamine and its receptors: therapeutic applications in sleep disorders
Insomnia is one of the most common disturbances of the sleep–wake cycle, whereas other pathologies such as hypersomnia and narcolepsy are less common. Insomnia is usually treated with short-lived benzodiazepines. However, the H1R is probably the most important physiological histamine target in the maintenance of waking. In animal studies, H1R agonists increase wake duration. Mice genetically deprived of the H1R (H1R-KO) exhibit a disrupted circadian rhythm and decreased activity during the
The histaminergic system and cognitive processes: therapeutic challenges
Cognitive impairments are the dreadful hallmarks of neurodegenerative and psychiatric disorders. Most treatment strategies focus on a single neurotransmitter system, even though multiple neurotransmitter systems and brain circuits are presumably involved. This is the case for the treatment of AD, in which the primary therapeutic choices are acetylcholinesterase inhibitors (AChEIs) that provide only modest and short-lived symptomatic relief [47].
A unique and remarkable feature of H3R antagonists
Histamine system and eating behavior
The interest in the histaminergic system as a potential target for the treatment of feeding disorders is driven by the unsatisfactory history of the pharmacotherapy of obesity. The drugs currently available for long-term treatment of obesity such as sibutramine, a monoamine reuptake inhibitor, and orlistat, a peripherally acting lipase inhibitor, work by different mechanisms, reflecting the complex etiology of the disease. Various combination therapies targeting disparate systems are also
Concluding remarks
The discoveries of H1R and H2R antagonists, both blockbuster drug classes for treating allergic conditions and GERD, respectively, were acknowledged with the Nobel prizes to Bovet in 1957 and Black in 1988. The discovery of the H3R by Schwartz and his group in 1983 [3] was greeted with considerable excitement, and its potential therapeutic role soon became clear as selective receptor agonists, antagonists and, more recently, inverse agonists were developed. All four histamine receptors are
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